Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury

靶向 MicroRNA miR-122 治疗围手术期肝损伤

• 批准号: 9980672
• 负责人: Holger K. Eltzschig
• 金额: $ 47.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980672
• 关键词: Acute; Address; Attenuated; Binding; Biological Assay; Cadaver; Cell Line; Clinical Research; Excision; Exposure to; Family; Gene Expression; Genes; Genetic Transcription; Goals; HIF1A gene; Hepatic; Hepatic Tissue; Hepatitis C virus; Hepatocyte; Human; Hypoxia; Injury; Length; Liver; Living Donors; Mediating; MicroRNAs; Modality; Morbidity - disease rate; Mus; Nucleotides; Operative Surgical Procedures; Oxygen; Pathway interactions; Patients; Perioperative; Procollagen-Proline Dioxygenase; Reperfusion Injury; Reperfusion Therapy; Repression; Resistance; Role; Signal Transduction; Small Interfering RNA; Source; Therapeutic; Transcriptional Regulation; Translating; Untranslated RNA; Up-Regulation; attenuation; base; design; graft failure; inhibitor/antagonist; innovation; lentiviral-mediated; liver biopsy; liver injury; liver ischemia; liver transplantation; mortality; mouse model; nanoparticle; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; prevent; promoter; protein expression; reconstitution; safety and feasibility; tissue injury; transcription factor

PROJECT SUMMARY The goal of this proposal is to identify microRNA (miRNA) targets as innovative therapeutic approach for the treatment of hepatic ischemia and reperfusion injury. Hepatic ischemia and reperfusion injury is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. MiRNAs constitute a family of noncoding RNA molecules of 20 to 25 nucleotides in length that regulate gene expression at the posttranscriptional level. In order to identify functionally important miRNAs during hepatic ischemia and reperfusion, we performed a targeted miRNA screen in a murine model of liver ischemia. We observed the most dramatic increase in miRNA expression for miR-122 – a liver-specific miRNA that is functionally implicated in the propagation of the hepatitis C virus. Subsequent studies of hepatic ischemia and reperfusion injury in mice with hepatocyte-specific deletion of miR-122 revealed dramatic increases in hepatic tissue injury. Utilization of a hepatocyte cell line with lentiviral-mediated overexpression of miR-122 allowed us to identify the oxygen-sensing prolyl-hydroxylase PHD1 as a novel target gene for miR-122. Thus, we hypothesize that HIF1A-dependent induction of miR-122 represents a feed-forward pathway for liver protection that enhances hypoxia-elicited liver protection via repression of its target gene PHD1.

项目摘要 该提案的目标是确定microRNA（miRNA）靶点，作为治疗糖尿病的创新方法。 肝缺血再灌注损伤的治疗。肝脏缺血再灌注损伤是一个重要的 主要肝切除术和肝移植期间发病率和死亡率的来源。miRNAs 组成一个20到25个核苷酸长的非编码RNA分子家族，其调节基因表达 在转录后水平。为了鉴定在肝缺血和肝硬化过程中具有重要功能的miRNAs， 在再灌注后，我们在小鼠肝缺血模型中进行了靶向miRNA筛选。观察了 miR-122的miRNA表达增加最显著，miR-122是一种肝脏特异性miRNA， 与丙型肝炎病毒的传播有关。肝脏缺血和再灌注的后续研究 肝细胞特异性缺失miR-122的小鼠中的损伤显示肝组织损伤显著增加。 利用慢病毒介导的miR-122过表达的肝细胞系，我们可以鉴定出miR-122在肝细胞中的表达。 氧敏感脯氨酰羟化酶PHD 1作为miR-122的新靶基因。因此，我们假设， HIF-1A依赖性诱导miR-122代表了一种肝保护的前馈途径， 缺氧通过抑制其靶基因PHD 1而引起肝保护。